Pharmaceutical composition for inhalation

ABSTRACT

The present invention relates to a powder formulation which reduces side effect risk of a medicine having a side effect of drug-induced photodermatosis and increases therapeutic effect, and relates to the method for producing the same. 
     Said powder formulation makes inhalation therapy possible by carrying out aerosolization easily, and since pharmacological effect in lung local part is increased, it is possible to decrease the dose. Skin transmigration of said medicine is controlled by a lung specific delivery technology, and photodermatosis which is a side effect can be controlled.

TECHNICAL FIELD

Present invention relates to a pharmaceutical composition which cancontrol the whole body exposure of a medicine, especially transmigrationto skin of a medicine having a side effect of drug-inducedphotodermatosis. The present invention also relates to a respirablepowder formulation which is easy to be handled pharmaceutically andmakes it possible to retain the uniform drug content because ofimprovement in dispersibility.

BACKGROUND ART

Inhalation therapy has been applied for treatment of lung andrespiratory tract disease, diagnosis of disease, transrespiratory tractand transpulmonary whole body medication, prophylaxis of disease,transrespiratory tract immunity desensitization therapy, etc. as amedicinal use of transrespiratory. However, the adaptation-determiningmethod of this therapy is fully examined at neither of the cases.Therefore, development of the corresponding respirable formulation isdesired.

As features of a general respirable formulation, recognized are 1) quickexpression of drug effects, 2) gradual reduction of side effects, 3)possibility of small dose administration, 4) avoidance of the first-passeffect, etc. When a target region is lung, the respirable formulation isequipped with further outstanding features by having a large surfacearea equal to small intestine. In applying the respirable formulation asa targeting therapy, it is necessary to consider a selection-criteriamethod of the respirable formulation from viewpoint of not only efficacyto disease but a generation method of medicine particles, arrival parts,and relevancy of the basic physical properties of medicine to them. Now,the respirable formulation is used for bronchodilator, mucosasolubilizer, antibiotic, antiallergic agent, steroid, vaccine,physiological saline, etc., and in the case of their clinicalapplication, site of action of inhalant, mechanism of the action,composition, direction for use, etc. are considered to be of importantfactors.

Recent years, in treatment of bronchial asthma or chronic lung disease,a Dry Powder Inhaler (Dry Powder Inhaler, DPI) has come to attractattention. This form has advantage that, in addition of the feature asabove-mentioned respirable formulation, medicine can be stored withstable form for a long period of time. In DPI, there is a closerelationship between a particle diameter of medicine particles beingrespired by patient and a deposition to respiratory tract [Pharmacia(1997) Vol. 33, No. 6, and 98-102], and the aerodynamics correlation isaccepted in what kind of medicine particle diameter deposits insidetrachea and lung. Specifically, it is generally known that the optimalsizes of medicine particles which can reach bronchus or lung areparticles which have an aerodynamics diameter of about 1 to 6 μm [Int.J. Pharm. (1994) 101 and 1-13].

Preferably, particles of several μm or less reach alveolus, and sincethey are efficiently absorbed from lung mucosa and migrate into blood,the particle size becomes important. However, the more the particles getfine, the more the fluidity of powder gets worse and, as a result,decline of filling precision and handling property at the time ofproduction gets worried. Then, in order to solve these problems inhandling of the DPI formulation, the method mentioned below is wellknown which mixes micronized particles with coarse particles, such aslactose and erythritol, being used as carrier. According to this method,by making micronized particles adhere to the carrier surface viaintermolecular interaction, cohesive force of micronized particlesbecome weaker, and the particle diameter becomes large further as awhole, and thus, the fluidity of the formulation is improved. The othermethods including granulation of a medicine and a surface treatmentmethod are mentioned (Patent Document 1).

Here, pirfenidone (henceforth PFD) is the world's first anti-fibrosisagent for approval acquisition to be applied for idiopathic pulmonaryfibrosis. The action mechanism is production modulation for variouscytokines, such as inflammatory cytokine and anti-inflammation cytokine,and for growth factors which participate in fibrosis formation, and theanti-fibrosis effect is shown based on complex effects, such asfibroblast multiplication depressant action and collagen productiondepressant action. In comparison between this agent and prednisolone,while prednisolone showed only anti-inflammatory activity, this agentshowed both anti-inflammatory activity and anti-fibrosis effect, then,consequently, it is expected that more effective therapeutic resultsthan steroid can be brought about. Although it has been sold since 2008in Japan, and is widely used for pulmonary fibrosis, many of patientswho have taken this agent have showed a side effect of drug-inducedphotodermatosis, and their expression frequency results in about 60percent. In order to avoid this problem, suitable dosage form which caneasily show effect on lung local part has been desired. However, onlyoral formulation has been marketed till the present, and more preferabledosage form design aiming at stability and local administration has notbeen examined irrespective of the high demand. That is, development isdesired strongly for new dosage forms which will reduce photodermatosisrisk, a side effect of pirfenidone, and will bring about safer pulmonaryfibrosis treatment. As DPI formulations in which micronized particleswere made to adhere to the carrier surface, a formulation using lactoseas a carrier (Patent Document 2), a cyclosporin formulation (Non-patentDocument 1), a tranilast formulation (Patent Document 3, Non-patentDocuments 2-3), etc. have been reported. However, in any references, thetransmigration control to the skin and the photodermatosis risk fall ofmedicine by the above-mentioned DPI formulation are not described.

LIST OF PRIOR ARTS

-   [Patent Document 1] WO99/27911-   [Patent Document 2] Japanese Patent 4125512-   [Patent Document 3] Japanese Patent Publication 20 1-93849 A-   [Non-patent Document 1] Journal of Controlled Release (2009), 38(1),    16-23-   [Non-patent Document 2] Journal of Pharmaceutical Sciences (2011),    100(2), 622-633-   [Non-patent Document 3] European Journal of Pharmaceutics and    Biopharmaceutics (2011) 77(1) 178-181

SUMMARY OF INVENTION Problems to be Solved by the Invention

Medicines migrate to the whole body generally via blood by oraladministration, then accordingly, they migrate also to the skin to someextent, and this is thought to causes a side effect. Accordingly, asubject of the invention is to provide a formulation which can controlthe whole body exposure of a medicine having a side effect ofdrug-induced photodermatosis, especially transmigration of the medicineto the skin. Still more preferably is a provision of a respirableformulation wherein the medicine, especially pirfenidone, shows asufficient efficacy and outstanding inhalation characteristics.

Means for Solving the Problems

Inventors of the present invention repeated researches extensively tosolve the above-mentioned problems, and as a result, they came tocomplete the present invention. That is, pirfenidone, which is amedicine having a side effect of drug-induced photodermatosis, wasground by a grinder such as a jet mill in the coexistence of excipientsto afford micronized particles having a diameter which can reach lungaerodynamically, and subsequently, the micronized particles obtainedwere mixed well with carriers which have a good conformity with theobtained-micronized particles and have a diameter which can reachsystems respiratorium aerodynamically, then a formulation with very highcontent-uniformity was successfully obtained to complete the presentinvention. When an experimental lung inflammation model rat wasmedicated with this formulation in respiratory tract, while a controlgroup showed very high lung disorder property and neutrophilic-leukocyteinflammation, a group administered with pirfenidone in a respirableformulation was able to be controlled powerfully against theseconditions. When pirfenidone of dose (30 mg/kg) which does not showanti-inflammatory activity was administered orally to rat,photodermatosis was not caused, but transmigration to the skin wasobserved promptly. On the other hand, when pharmacologically effectivedose, for example, of 0.1 mg/kg or more of the respirable powderformulation of pirfenidone was administered to the subject inrespiratory tract, as compared with oral administration, significantsuppression of the skin extraction rate was observed. From these data,it can be said that the respirable powder formulation of the presentinvention decreases dose remarkably by delivering a medicine directly tothe pharmacodynamic target tissue, and moreover, in connection with it,the formulation shows such a prominent effect that a drug-inducedphotodermatosis risk which is a critical side effect may be reduced.That is, the present invention provides the followings (1)-(22).

-   (1) A powder formulation comprising micronized particles with a mean    particle diameter of 20 μm or less comprising a drug having a side    effect of drug-induced photodermatosis and an excipient, and a    carrier having a mean particle diameter of 10˜200 μm.-   (2) The powder formulation according to (1) above, wherein the drug    having a side effect of drug-induced photodermatosis is 1 or 2 or    more selected from the group consisting of antibiotics, anticancer    drug, antiepileptic drug, antidepressant, antifungal, antihistamine,    antimalarial, gout drug, psychotropic drug, cardiovascular remedy,    diuretic, antilipemic, non-steroid anti-inflammatory agent,    phototherapy agent, letinoid, and pulmonary fibrosis treating agent.-   (3) The powder formulation according to (1) above, wherein the drug    having a side effect of drug-induced photodermatosis is a pulmonary    fibrosis treating agent.-   (4) The powder formulation according to (1) above, wherein the drug    having a side effect of drug-induced photodermatosis is pirfenidone.-   (5) The powder formulation according to any one of (1)-(4) above,    wherein the micronized particles and the carriers form complexes.-   (6) The powder formulation according to (5) above, wherein a    particle diameter of the micronized particles is smaller than a mean    particle diameter of the carriers.-   (7) The powder formulation according to any one of (1)-(6) above,    wherein the excipient and/or the carrier are saccharides.-   (8) The powder formulation according to (7) above, wherein    saccharides are lactose.-   (9) The powder formulation according to any one of (1)-(6) above,    wherein the excipient and/or the carrier are sugar alcohols.-   (10) The powder formulation according to (9) above, wherein the    sugar alcohols are erythritol.-   (11) The powder formulation according to any one of (1)-(6) above,    wherein the excipient is macromolecular polymers.-   (12) The powder formulation according to any one of (1)-(6) above,    wherein the excipient is erythritol and the carrier is lactose.-   (13) The powder formulation according to any one of (1)-(12) above,    wherein a ratio between the drug having side effects of drug-induced    photodermatosis and the excipient is in the range of 1:5000˜10:1 in    weight ratio.-   (14) The powder formulation according to any one of (1)-(13) above,    wherein the ratio between the micronized particles and the carriers    is in the range of 1:100˜10:1 in weight ratio.-   (15) The powder formulation according to any one of (1)-(14) above,    wherein a mean diameter of the micronized particles is in the range    of 1˜9 μm.-   (16) The powder formulation according to any one of (1)-(15) above,    wherein the powder formulation is a transpulmonary respirable    formulation.-   (17) The powder formulation according to (4) above, wherein the    drug-induced photodermatosis of pirfenidone has been reduced as    compared with an oral administration formulation.-   (18) A process for producing the formulation according to any one of    (1)-(17) above, wherein the micronized particles with a mean    particle diameter of 20 μm or less comprising a drug having a side    effect of drug-induced photodermatosis and an excipient are mixed    with a carrier having a particle diameter of 10˜200 μm.-   (19) The process according to (18) above, wherein the micronized    particles are prepared by mixing the drug having a side effect of    drug-induced photodermatosis and the excipient, and micronizing the    mixture by a jet mill.-   (20) The process according to (19) above, wherein the micronized    particles and the carriers are mixed in a container made from nylon    or polyethylene.-   (21) The process according to any one of (18)-(20) above, wherein    the micronized particles and the carriers form complexes.-   (22) A respirable formulation obtained by the process according to    any one of (18)-(21) above.

EFFECTS OF THE INVENTION

According to the pharmaceutical composition of the present invention, itis possible to aerosolize easily a medicine powder, such as pirfenidone,which has a side effect of drug-induced photodermatosis, and bydelivering the medicine very specifically to lung, treatment ofinflammatory lung disease, pulmonary fibrosis, etc. is remarkablyenabled by low dose compared with an oral administration, andsimultaneously, by preventing a skin transmigration of the medicine, itis possible to reduce the photodermatosis risk which is a main sideeffect of the medicine. And, the pharmaceutical composition of thepresent invention can be produced more preferably as a uniform-contentformulation.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a particle size distribution at the time when theformulation 1 was aerosolized.

FIG. 2 shows a SEM image at the time when carriers and micronizedparticles (excipient and pirfenidone particles) formed complexes.

FIG. 3 shows the result of photoreactivity test of each compound. InFIG. 3(A), the symbols represent: □/▪: pirfenidone, ∇/▾: 8-methoxypsoralen (MOP), and Δ/▴: sulisobenzone (□∇/Δ are singlet oxygen and ▪▾▴are superoxide). In FIG. 3(B), symbols represent: □: pirfenidonesolution, ⋄: pirfenidone powder, and : respirable powder formulation ofpirfenidone.

FIG. 4 shows the amount of pirfenidone in each stage in the body ofcascade impactor in the case of use or non-use of the carrier.

FIG. 5 shows a counting result of inflammatory cells in a bronchoalveolar lavage fluid (BALF) of an asthma and chronic obstructivepulmonary disease model rat being administered with the formulation 1 byinhalation.

FIG. 6 shows results of biomarker measurement result of inflammatorycells in broncho alveolar lavage fluid (BALF) of the asthma and chronicobstructive pulmonary disease model rat being administered with theformulation 1 by inhalation.

FIG. 7 shows the amount of transmigration of pirfenidone to each tissueat the time of carrying out single-dose administration of the oral andrespirable formulations. Symbols represent; A: oral pirfenidone 160mg/kg, ∇: oral pirfenidone 30 mg/kg, and : 1 mg/kg of the respirablepowder formulation of pirfenidone.

FIG. 8 shows a concentration change of pirfenidone in skin at the timeof administering oral and respirable formulations repeatedly. Symbolsrepresent; Δ:oral pirfenidone 160 mg/kg, ∇: oral pirfenidone 30 mg/kg,and : 1 mg/kg of the respirable powder formulation of pirfenidone.

EMBODIMENTS TO CARRY OUT THE INVENTION

Hereinafter, the present invention is explained in detail. [1] Medicinehaving a side effect of drug-induced photodermatosis Especially asmedicines having a side effect of drug-induced photodermatosis, althoughnot limited specifically, the medicines described in Table 2 of CurrentDrug Safety, (2009), vol 4, pp 123-126 are mentioned. For example, theyare antibiotic, anticancer agent, antiepileptic drug, antidepressant,antifungal, antihistamine, antimalaric, gout drug, psychotropic drug,cardiovascular treating agent, diuretic, antilipemic, non-steroidanti-inflammatory agent, phototherapy agent, letinoid, pulmonaryfibrosis treating agent, etc. Ciprofloxacin, enoxacin, lemefloxacin,sulfanilamide, sulfamethoxazole, tetracycline, etc. are mentioned asantibiotic. Fluorouracil, methotrexate, etc. are mentioned as theanticancer agent. Carbamazepine, phenobarbital, etc. are mentioned asthe antiepileptic drug. Amitriptyline, amoxapine, etc. are mentioned asthe antidepressant. Flucytosine, itraconazole, etc. are mentioned as theantifungal. Bromapheniramine, diphenhydramine, etc. are mentioned as theantihistamine. Chloroquine, kinin, etc. are mentioned as theantimalaric. Benzbromarone etc. are mentioned as the gout suppressant.Chlorpromazine, haloperidol, etc. are mentioned as the psychotropicdrug. Captopril, clofibrate, etc. are mentioned as the cardiovasculartreating agent. Furosemide, acetazolamide, etc. are mentioned as thediuretic. Glibenclamide, tolbutamide, etc. are mentioned as theantilipemic. Indomethacin, ibuprofen, etc. are mentioned as thenon-steroid anti-inflammatory agent. 8-MOP (xanthotoxin), foscan,photofrin, etc. are mentioned as the phototherapy agent. Acitretin,etretinate, isotretinoin, etc. are mentioned as the letinoid.Pirfenidone is mentioned, for example, as a treatment agent forpulmonary fibrosis. In the present invention, pirfenidone is especiallypreferable. As pirfenidone being used in the present invention, themethod of preparing the same is not limited in particular, and what isused or will be used in the future as drugs is included, such ascrystal, amorphous, salt, hydrate, and solvate thereof.

[2] Excipient

The excipient used herein is the one which is generally used for thepurpose of gain in weight, dilution, filling, supporting of form, etc.of solid preparations, such as powders and a tablet. The excipient iseffective in order to improve the solubility of a medicine, and/or toreduce the self-condensation ability of a medicine. Accordingly,although a water-soluble excipient is preferred, the excipient whichabsorbs moisture remarkably is not preferred for the property of thisformulation. The excipient which is biologically inactive and isexpected to be metabolized to some extent may be used. Water-solublepolymers can also be used, and there is no limitation for them as far asthey are allowable as a medicine. A combination of one or more sortsselected from these may be used. Preferable excipients in the presentinvention are one or more selected from the group consisting of sugars,sugar-alcohols, macromolecular polymers and calcium carbonates, andlactose or saccharose is preferable as sugars, erythritol, sorbitol, ormannitol is preferable as sugar-alcohols, and carmellose calcium,pullulan, polyvinylpyrrolidone, or methylcellulose is preferable asmacromolecular polymers. Especially preferable excipient is lactose orerythritol.

[3] Carrier

In the present invention, a carrier is used for preventing the medicineto condense before the administration of the powder formulation, and forimproving absorption efficiency as the transpulmonary respirableformulation at the time of administration, by forming a complex betweenthe medicine and the excipient (mentioned afterward). Especially, whenan inhalation operation using an inhaler is carried out for the purposeof application in bronchus or lung, the inhaler is used for efficientlyseparating the excipient from the medicine after inhalation and, as aresult, for improving absorption efficiency of the medicine. When thecarrier is used for DPI formulation design, it is desirable to releasethe medicine definitely from the capsule or device, and to separate themedicine from the carrier surface with high probability. It is necessaryto perform the formulation design in considering enough these points. Inthe case of using carriers, fluidity of the formulation, prevention ofthe medicine aggregation, and the propriety of dose increase anddecrease, etc. become important. From these viewpoints, carriers in thepresent invention are preferably powdered. As selection criteria ofcarriers, easiness and workability for handling are required, not tomention toxicity or physicochemical stability. In order to clear theseproblems, lactose, the stability of which is also establishedconventionally, and is neutral, has little reactivity, and also hassweet taste a little, is useful in many points, and its usefulness isconfirmed as the carrier for DPI [Int. J. Pharm. (1998) 172, 179-188].As carriers which can be used in the present invention, sugars such asgrape sugar, fructose, saccharose, maltose and dextran besides lactose,sugar-alcohols such as erythritol, sorbitol, and mannitol, commonexcipients such as calcium sulfate, calcium carbonate, talc, andtitanium oxide can be mentioned also, and there is no limitation inparticular. Preferable carrier is sugars or sugar-alcohols, and morepreferable carrier is lactose or erythritol and, lactose is especiallypreferable.

When the pharmaceutical composition of the present invention is a formbeing administered to the patient using an inhaler, the carrier is theone which has a particle diameter permitted aerodynamically.Specifically, a range of the mean particle diameter of the carrier is10˜200 μm.

When you want to make the carrier act only as a carrier from the pointof dosage form design, it is known that enlarging of the particlediameter is enough for it. However, simultaneously, if the particlediameter is enlarged, it is also a well-known fact that the carrierretains at throat or the oral cavity. Accordingly, when it is moredesirable to prevent the carrier itself from reaching even lung in spiteof its biological inactivity, it is satisfactory if the mean particlediameter shall be at least 10 μm or more. When further best conditionsare required, material selection after considering the conformity etc.of a main agent and a mixed excipient is desired. However, unless bigproblems are observed in particular, it is preferable to select acarrier of the same quality of material as that of the excipient.

[4] Mixing and grinding process of the medicine having a side effect ofdrug-induced photodermatosis and the excipient Manufacture of the powderformulation for inhalation administration of the present inventioncontains a mixing and grinding process of the medicine having a sideeffect of drug-induced photodermatosis and the excipient. Trituration isperformed, for example, at the same time as the excipient and themedicine having a side effect of drug-induced photodermatosis are mixedusing an aerodynamic grinder. The method is not limited for producingthe powder formulation of the present invention, but a suitable methodwhich a person skilled in the art usually uses can be used. It can besuitably determined by the kinds of medicine and excipient, the size offinal particles, etc. whether which method is used or not. Acrystallized state of the compound and the formulation characteristics,such as adhesion and dispersing ability, are correlated in many cases,and, consequently the latter processing method should be selecteddesirably in this step. However, in the case where pirfenidone is usedas the medicine expressing a side effect of drug-inducedphotodermatosis, and erythritol is used as the excipient, because of thevery high crystal orientation of pirfenidone, a good trituration mixturecan be obtained even if any step is selected.

Particles which comprise the obtained medicine and excipient accordingto the above-mentioned step are called micronized particles in thisspecification.

In the present invention, although a general drying-grinding process canbe used for trituration of the medicine and the excipient, it ispreferred to use especially an aerodynamic grinder. Specifically,devices which grind small quantity efficiently in a laboratory, such asa mortar and a ball mill, are used frequently as a commondrying-grinding machine. As a ball mill, a rolling ball mill, acentrifugal ball mill, a vibration ball mill, and a planetary ball millare known, and these can perform trituration by principles, such asgrinding, rotation, vibration, and impact. There are many devices, asindustrial use, aiming at efficiently grinding a lot of materials, suchas a medium churning type mill a high velocity revolution triturationand impact mill, and a jet mill. There are a disc mill and a roller millas a high velocity revolution trituration mill, and as a high velocityrevolution impact mill, there are devices such as a cutter mill (knifemill), a hammer mill (atomizer), a pin mill, a screen mill, etc., whichperform trituration also according to rotation impact in addition toshearing. As a jet mill, many mainly perform trituration with impact. Asfor the kind, there are the most orthodox particle-particle collisiontype, a particle-collision plate collision type, and a nozzle suckingtype (blow off). In particular, it is preferred that the trituration isperformed by the jet mill.

As for a weight ratio of the medicine having a side effect ofdrug-induced photodermatosis and the excipient in the formulation of thepresent invention, a range of 1:5000˜10:1 is preferable. If the medicineincreases more than this range, trouble may result in the contentuniformity, and if the excipient increases more than this range, for acertain kind of medicine, there is a danger of elimination of thepharmacological activity. The weight ratio of the medicine having a sideeffect of drug-induced photodermatosis and the excipient is morepreferably 1:100˜5:1, and still more preferably, 1:10˜2:1, and mostpreferably, 3:2.

By grinding process, the medicine having a side effect of drug-inducedphotodermatosis is mixed with the excipient by homogeneity, and it isground so that the mean particle diameter may become micronizedparticles of 20 μm or less. The diameter within these ranges makes itpossible for the micronized particles to reach the part of objects, suchas bronchus and lung. Mean particle diameter of micronized particles is10 μm or less, preferably, 1˜9 μm, more preferably, and 3μ8 μm, mostpreferably.

[5] Mixing step of carriers and micronized particles Subsequently, themicronized particles obtained in the above-mentioned mixing/triturationstep are mixed with carriers, and till the time of administration, andlet stable complexes to be formed. In the specification of the presentapplication, the complex represents a molecular aggregate formed bycondensation of a medicine with an excipient and a carrier viaself-condensation capability caused by a molecular interaction of themedicines. Mixing of carriers and micronized particles can be performedby using a well-known mixer generally. There are mainly a batch systemand a continuous system in the mixer, and further in the batch system,there are two sorts of a rotated type and a fixed mount type. There area horizontal drum mixer, a V shaped rotary mixer, a double cone typemixer, and a cubic type mixer in the rotated type, and there are a screwtype (perpendicularity, level) mixer, a revolution screw type mixer, anda ribbon type (perpendicularity, level) mixer in the fixed mount type.The continuous system is also divided into two sorts, a rotated type anda fixed mount type. As for the rotated type, a horizontal drum mixer anda level cone type mixer are known, and a screw type (perpendicularity,level) mixer, a ribbon type (perpendicularity, level) mixer, and arotation disk type mixer are known for the fixed mount type. Inaddition, the mixing method using aerodynamic grinders, such as a mediumchurning type mill, a high velocity revolution grinding and an impactmill, and a jet mill, is possible. It is possible to make a uniformmixed-preparation by using and agitating a container which consists ofproduct made of nylon, polyethylene, or the material having propertysimilar to them.

It is preferred to make the weight ratio of micronized particles andcarriers into the range of 1:100˜10:1. If the micronized particlesincrease more than this range, trouble may result in the contentuniformity, and if the carriers increase more than this range, for acertain kind of medicine, elimination of the pharmacological activity isworried about. Weight ratios of micronized particles and carriers aremore preferably 1:50˜1:1, still more preferably 1:20˜1:5 and mostpreferably 1:10.

A ratio of mean particle diameters of micronized particles and carriersis preferably in the range of 1:1˜1:50, and more preferably 1:5˜1:20.

[6] Inhaler

When the complex obtained in the above-mentioned step is administered toa patient as the powder formulation for inhalation administration, thesubject can be medicated by per-mucosal administration such astranspulmonary administration, nasal administration, etc. When the routeof administration is transpulmonary administration, specifically, thepowder formulation can be prescribed for the patient by using anyinhalers generally used in the art.

As the inhaler, devices for inhalation transpulmonary, such as Spinhaler, E-haler, Flow-Caps, Jet haler, Disk haler, Rotor haler, Inspirerease, Inhalation eight, etc. and quantitative atomizers, etc., can beused but it is not limited to these.

EXAMPLE 1

(1) Preparation of Micronized Particles Used for Respirable PowderFormulation

After mixing a pirfenidone crystal (about 60 mg) with various excipients(about 40 mg), micronization was performed with a jet mill, and thus,micronized particles were prepared. As the excipient, erythritol (Nikkenformation), lactose (DMV), carmellose calcium (Daicel ChemicalIndustries), pullulan (Hayashibara), polyvinyl pyrrolidone (BASF),methyl cellulose (Shin-Etsu Chemical), sorbitol (Kao), calcium carbonate(Kanto Kagaku) or white soft sugar (Mitsui Sugar) was used,

(Grinding Conditions)

-   Used instrument: A-O-Jet Mill (Seishin Enterprise)-   Feeding method: Auto feeder-   Supply air pressure: 6.0 kg/cm²G-   Grinding air pressure: 6.5 kg/cm²G-   Dust collecting method: Outlet bug (polyethylene)

The yield was as follows, respectively.

Micronized particles 1 (excipient: erythritol) 75.8% Micronizedparticles 2 (excipient: lactose) 61.0% Micronized particles 3(excipient: carmellose sodium) 59.9% Micronized particles 4 (excipient:pullulan) 74.6% Micronized particles 5 (excipient: polyvinylpyrrolidone) 68.5% Micronized particles 6 (excipient: methyl cellulose)71.3% Micronized particles 7 (excipient: sorbitol) 88.3% Micronizedparticles 8 (excipient: mannitol) 68.4% Micronized particles 9(excipient: calcium carbonate) 72.9% Micronized particles 10 (excipient:white soft sugar) 60.8%

(2) Preparation of Respirable Powder Formulation

The micronized particles obtained in (1) were put into a STAT-3Santistatic bag made from polyethylene (20×30 cm, Asanuma industrialCorporation Ltd.) with carriers, and sealed after being filled with air,and the content was mixed by shaking by hand for about 3 minutes, thenthe formulations 1-20 shown in. Table 1 were obtained. Samples weretaken from five places arbitrarily after mixing, the amount of the drugcontained was measured by UPLC/ESI-MS, and the uniformity of the contentwas thus confirmed. At this time, erythritol (Nikken formation, meanparticle diameter: 20˜30 μm) or lactose (DMV, mean particle diameter:50˜60 μm) was used as carriers. The weight ratio of the micronizedparticles and the carriers was 1:10.

EXAMPLE 2

Particle-Size-Distribution Measurement of Respirable Powder Formulation

As a result of evaluating the mixture of micronized particles andcarriers using a dry type laser diffraction device (LMS-300, SeishinEnterprise), aerosolization of any formulation was easily carried outunder pressure of 0.2 MPa. FIG. 1 shows a particle size distribution ofthe mixture (formulation 1) of the micronized particles 1 and lactosecarriers. Two main peaks are mainly shown, and the peak with a meanparticle diameter of 7 μm originates in the micronized particles, andthe peak with a mean particle diameter of 60 μm originates in thecarriers. As for other formulations, the ranges of a mean particlediameter of the micronized particles were 3.0˜8.0 μm. It is consideredthat the carriers remain in respiratory tract at the time of inhalation,and the micronized particles may reach bronchus or lung at the time ofinhalation. The mean particle diameters of the micronized particles inthe formulations 1˜20 obtained by analysis are shown in Table 1. The SEMimage which photographed the situation where the micronized particles(excipient and pirfenidone grains) were actually complexed with carriers(lactose) is shown (FIG. 2). It can be observed that the pirfenidonegrains, which were micronized by jet milling and turned into singlespherical grains, adhered to lactose without any significantagglomeration.

TABLE 1 Mean paraticle diameter of Micronized Excipient Carrierparticles (μm) Formulation 1 erythritol lactose 7.0 Formulation 2lactose lactose 5.6 Formulation 3 carmellose lactose 7.1 Formulation 4pullulan lactose 6.4 Formulation 5 polyvinylpyrrolidone lactose 6.5Formulation 6 methyl cellulose lactose 7.3 Formulation 7 sorbitollactose 3.7 Formulation 8 mannitol lactose 6.2 Formulation 9 calciumcarbonate lactose 7.8 Formulation 10 saccharose lactose 4.6 Formulation11 erythritol erythritol 5.3 Formulation 12 lactose erythritol 7.6Formulation 13 carmellose erythritol 3.8 Formulation 14 pullulanerythritol 5.6 Formulation 15 polyvinylpyrrolidone erythritol 4.1Formulation 16 methyl cellulose erythritol 3.3 Formulation 17 sorbitolerythritol 7.4 Formulation 18 mannitol erythritol 4.8 Formulation 19calcium carbonate erythritol 6.2 Formulation 20 saccharose erythritol3.6

EXAMPLE 3

Photoreactivity Testing and Photostability Testing

FIG. 3(A) shows the result of a reactive oxygen species (ROS) assaywhich was carried out to measure the photoreactivity of pirfenidone.This assay was established to monitor the generation of ROS, such assinglet oxygen and superoxide, from photoirradiated chemicals, and ROSgeneration would be indicative of the photochemical reactivity of testedchemicals. Sulisobenzone, a potent UV absorber, has no ability togenerate ROS when exposed to simulated sunlight (250 W/m²); therefore,sulisobenzone can be identified to be less photoreactive. In contrast,8-methoxypsoralen (MOP) is known as a phototoxic and photoreactivechemical. Although 8-MOP slightly exceeded pirfenidone in ROSgeneration, both chemicals were identified to be photoreactive, as shownin FIG. 3(A). When such photoreactivity and photoirritability are takeninto consideration, pirfenidone can be said to raise concerns aboutphotostability. Here, in respirable formulation of pirfenidone, bothliquid and dry powder formulations can be considered in theory. Then, toclarify the photochemical properties in more detail, photostabilitytesting was carried out. First, none of the pirfenidone samples testedshowed any degradation in chromatographic analysis when they were storedat 25° C. for 1 h under light protection. Exposure of PFD solution tosimulated sunlight (250 W/m²) resulted in the degradation ofpirfenidone, and it was likely to follow first-order kinetics with anapparent first-order degradation rate of 0.31±0.03 h⁻¹ as shown in FIG.3(B). In contrast, no significant degradation was observed inpirfenidone powder under the same irradiation conditions. In general,photosensitive chemicals in a solution state are far more prone tophotodegradation than solid samples due to the high permeability oflight and increased mobility of photochemically excited molecules andreactive species. From this, taken together with the result shown inFIG. 3(B), the respirable formulation of pirfenidone is preferable thanthe liquid formulation.

EXAMPLE 4

Assessment of the Respirable Powder Formulation (Formulation 1) byCascade Impactor

In order to conduct investigation on the aerodynamic particle size offine powders, an examination was carried out using a cascade impactorwhich is an artificial respiratory tract and a lung model. A body of theimpactor is composed of piles in eight stages and a final filter,combined with a velocity indicator and a suction pump. The fundamentalmethod, which is a procedure described in “Multistage Cascade ImpactorApparatus” of USP 2000 “Physical Tests and Determinations/Aerosols” wasapplied. The specified method is as follows.

(Method)

Apparatus: Andersen sampler (AN-200, product of Shibata chemicals)

Pump flow rate: 28.3 L/min

Device used: Jet-Haler (made by UNISIA JECS)

Sample: (i) formulation 1 respirable powder formulation

(Mixing ratio; micronized particles 1 ground by jet mill: carriers=1:10)

(ii) Micronized Particles 1

(ground by jet mill, but not mixed with carriers)

A Japanese Pharmacopoeia No. 2 capsule was filled up with samples (i)and (ii) in proper quantity, respectively, and was installed in thedevice.

Drug determination method: (UPLC-MS analysis conditions)

Column used: Acuity UPLC BEH C 18 Column (Waters)

Detector: SQ Detector (Waters)

Pump: Binary Solvent Manager (Waters)

Flow rate of mobile phase: 0.25 mL/min

Mobile phase: A: 100% acetonitrile, B: 5 mm ammonium acetate

-   -   0˜1 Min.: A 20%    -   1˜3 Min.: A 20-95%    -   3˜4 Min.: A 95%

Column temperature: 40° C.

(Results) The amount of pirfenidone in each stage in the body of cascadeimpactor is shown in FIG. 4. From assessment of aerodynamic particlesize by cascade impactor, as shown in the graph of FIG. 4(A), therespirable powder formulation (Formulation 1) of sample (i) was found tobe mainly distributed in the stage 0 and the stages 2˜4. The particlesdistributed in the stage 0 are estimated to be pirfenidone contained inthe undissociated complexes of micronized particles and carriers. Thedissociated micronized particles were found to be mainly distributed inthe stages 2˜4. The amount of per cents for particles distributed in thestages 2˜7 is defined by RF value specified as “a rate with whichmicronized particles arrive at a target site, bronchial tubes or lung.”The RF value in this Example exceeds 45%. Accordingly, it is thoughtthat the respirable formulation of the present invention, which is acomplex of micronized particles and carriers, remains in respiratorytract, and only micronized particles dissociated from the complex fullyreach the target site, bronchial tubes or lung. As to the release from acapsule, high fluidity and dispersibility of the formulation were alsoshown, since 98.6% of the formulation was confirmed to be emitted fromthe capsule. On the other hand, when the sample (ii), the micronizedparticles 1 using no carrier, was analyzed, about 99% remained in thestages 0 and 1, and the RF value was less than 1% as shown in the graphof FIG. 4(B). It is confirmed that sufficient dispersibility cannot beobtained without a carrier, and the fall of the inhalation propertieswas caused by forming agglomeration of the micronized particles.

Accordingly, in order to make the micronized particles reach the targetsite (bronchial tubes or lung), the powder respirable formulation usinga carrier is preferred.

EXAMPLE 5

(1) Preparation of a Model Animal Sensitized with Albumen OriginOvalbumin (OVA) and Medication of the Respirable Powder Formulation(Formulation 1) in Airway

Using an OVA-sensitized animal model which is a typical asthma andchronic obstructive pulmonary disease model, a medicinal effect of therespirable powder formulation of the formulation 1 was assessed. Thismodel causes local inflammation in the respiratory organ by prescribingthe OVA respirable powder formulation in airway of the animal sensitizedby the OVA acting as an antigen which causes neutrophilic leukocyteinflammation and eosinophilic leukocytosis in lung. The illustrativeprocedure of the model preparation and the medication in airway of therespirable powder formulation of the formulation 1 are shown below.

(Procedure)

Animal: Sprague-Dawley rat (8˜11 of age)

Reagents: Albumen origin ovalbumin (SIGMA) and aluminum hydroxide gel(SIGMA)

Medication instrument in airway: DP-4 (Ina Research, Inc.)

Animals were sensitized by intraperitoneal injection of the OVA solution(OVA: 0.33 mg/kg with 16.6 mg of alum) on days 0, 7, and 14. They werereceived intratracheal administration of the OVA respirable powderformulation (100 μg as OVA amount) at 24 h after the last OVAsensitization. The intratracheal administration was performed by sendingcompressed air through inserted DP-4 in the airway after anesthetizedwith sodium pentobarbital.

To the control group, a respirable powder formulatic a produced by usinglactose was used.

Pre-medication of the formulation 1 (1 mg kg) was performed 1 hourbefore medication of the OVA respirable powder formulation.

TABLE 2 before medication 24 hrs. after final sensitization OVA grouplactose-DPI OVA-DPI control goup lactose-DPI lactose-DPI Formulation 1group Formulation 1 OVA-DPI

(2) Bronchoalveolar Lavage Fluid (BALF) Collection, and Total CellNumbers in BALF

BALF is said to be useful for diagnosis of respiratory disease. In thisExample, inflammation and tissue disorders were assessed by counting thetotal cells in BALE. At 24 h after the OVA challenge, BALF was collectedby washing the airways with 5 mL of PBS by inserting cannula into theairway after brood removal from ventral aorta under anesthesia byNembutal. The BALF collected was pooled and centrifuged for 5 min, thesupernatant was then removed, and cells were re-suspended with 1 mL ofPBS. The total number of cells in BALF was counted using a manualhemocytometer under microscope.

FIG. 5 shows the result of measurement of the inflammatory cellinfiltration inhibiting activities by the formulation 1 (1 mg/kg) in anexperimental asthma and chronic obstructive pulmonary disease modelanimal. The ordinate shows total cell numbers in BALF. The total cellnumbers mainly consist of monocytes and neutrophils.

In the OVA group at 24 hours after the last sensitization, the totalcell numbers increased by about 6.5-fold compared to that of the controlgroup. On the other hand, in the formulation 1 group, the total cellnumbers in BALF decreased by about 90% as compared to those of thecontrol group.

Said inflammation decreased in a dose-dependent manner by pretreatmentwith the formulation 1 (0.1˜3.33 mg/kg), and the total cell numbers inBALF at the time of treatment by 3.33 mg/kg was almost equivalent to thecase of treatment by 1 mg/kg. These data were indicative of thetherapeutic potential of the formulation 1 against inflammation in thelung local part observed in pulmonary fibrosis, asthma, etc.

(3) Measurement of Lung Inflammation Injury Biomarkers in BALF

In order to examine the pharmacologic effect of the formulation 1 indetail, various biomarkers in BALF were measured. Lactate dehydrogenase(LDH) was chosen as a biomarker of lung disorder, and myeloperoxidase(MPO) was chosen as a biomarker of neutrophilic leukocyte inflammation,respectively. In inflammation and fibrosis of the airway, MPO secretedfrom neutrophilic leukocyte/macrophage works as a pro-inflammatorymediator. Accordingly, the enzyme activity of MPO functions as abiomarker of neutrophilic leukocyte.

Measurement results of LDH activity and MPO activity are shown in FIG.6.

As compared to the control group, both of the LDH activity and the MPOactivity in the OVA group at 24 hours after the last sensitizationincreased. On the other hand, in the formulation 1 group, reduction ofeach biomarker was observed as compared to the OVA group at 24 hoursafter the last sensitization. Specifically, an increase rate in whicheach biomarker increases from the control group by OVA sensitization wasattenuated by medication of the formulation 1 to about 67% in MPOactivity and to about 52% in LDH activity, respectively. Thus, theformulation is thought to be efficacious for suppression of neutrophilicinflammation and imbalance of the enzyme system accompanying with it.

These observations were in agreement with the inhibitory effects on therecruitment of inflammatory cells in BALF and thus, the present datawere also indicative of the topical therapeutic potential of theformulation 1 respirable powder formulation for the treatment ofpulmonary inflammatory and fibrotic diseases.

COMPARATIVE EXAMPLE 1

Examination of Phototoxic Reaction in Oral Administration of Pirfenidone

Hair of rats were carefully shaved by hair clipper, and pirfenidone wasadministered orally to the rats (160 mg/kg or 30 mg/kg), and the ratswere irradiated with a black light. Colors of the skin before and afterthe light irradiation were evaluated with a color difference meter. Theresults are shown in Table 3. Change of skin color was intentionallyobserved in the group medicated with 160 mg/kg of pirfenidone comparedto the control group, whereas significant change was not observed in thegroup medicated with 30 mg/kg of pirfenidone.

TABLE 3 evaluation of color change UV L* a* b*

 E control − initial value 64.91 1.26 7.19 1.13 ± 0.34 after treatment65.98 1.03 7.07 + initial value 71.22 1.30 2.29 2.26 ± 0.19 aftertreatment 69.23 1.92 3.03 pirfenidone − initial value 70.59 0.09 3.671.69 ± 0.24 (160 mg/kg) after treatment 71.04 −1.04 4.88 + initial value71.05 0.89 5.67 3.97 ± 0.59 after treatment 72.35 2.06 9.17 pirfenidone− initial value 70.16 1.19 −0.18 1.47 ± 0.27 (30 mg/kg) after treatment71.56 1.54 −0.36 + initial value 72.90 1.27 4.14 2.40 ± 0.20 aftertreatment 72.26 2.81 5.72

EXAMPLE 6

Pharmacokinetics (1) of Pirfenidone at the Time of Airway Administrationof the Formulation 1

The respirable powder formulation of pirfenidone resulted in markeddecrease in the amount of necessary dose as compared to the oraladministration. However, the possibility of risk reduction ofphotodermatosis is not clear. In general, since drug-inducedphotodermatosis appear in the skin and eyes, the specific distributionof drug molecules in the skin and/or eyes could be a key considerationfor evaluating the photodermatosis risk. Then, in order to verify thephotosafety of the formulation 1, a pharmacokinetic study was undertakenafter intratracheal administration of the formulation 1 at apharmacologically effective dose (1 mg/kg). Additionally, since in theoral administration, both pharmaceutically effective and phototoxic dose(160 mg/kg) and pharmaceutically non-effective and non-phototoxic dose(30 mg/kg) are known, pharmacokinetic parameters were obtained afteroral administration at both doses. Concentration-time curves ofpirfenidone in the plasma, skin, lung, and eyes were obtained byUPLC/ESI-MS analysis after intratracheal and oral administrations.Relevant pharmacokinetic parameters of pirfenidone, including C_(max),t_(1/2), AUC_(0, ∞), and MRT, were summarized in Table 4. After oraladministration of pirfenidone, plasma and lung concentrations ofpirfenidone immediately reached the C_(max) within 5 min and theseconcentrations decreased steadily with half lives of ca. 0.3-0.8 h. Withrespect to skin and eye depositions, reaching maximum levels at ca. 0.5h after oral dosing, followed by an elimination phase with a half-lifeof ca. 0.7-1.1 h. Thus, the elimination of pirfenidone from the skin andeyes was found to be slower than that in plasma and pirfenidone mayaccumulate in these light-exposed areas (skin and eyes) upon chronicdosing, resulting in an increased photodermatosis risk. In contrast,after intratracheal administration of the formulation 1, each of plasmaand tissue concentrations of pirfenidone immediately reached the C_(max)within 5 min, and then, these medicaments rapidly diminished belowdetectable levels within 1.5 h.

The intra airway administration of the formulation 1 (1 mg/kg) led toca. 440-, 90-, and 30-fold reductions in C_(max) values for plasma,skin, and eyes, respectively, compared to the orally-taken pirfenidoneat the photodermatosis expression dose (160 mg/kg). The AUC values inplasma, skin, and eyes decreased by ca. 1,800-, 370-, and 440-fold,respectively. From these studies, it was confirmed that theintratracheal administration of pirfenidone successfully resulted inmarked decrease in systemic exposure, compared to the oraladministration.

In addition, there were still ca. 63˜70-fold differences in AUC valuesfor skin and ocular pirfenidone between the oral formulation (30 mg/kg)and the respirable formulation (1 mg/kg) at non-photodermatosis level ofdoses. The differences of these pharmacodynamics coefficients show thatuse by inhalation of pirfenidone decreases notably the accumulation inskin and eyes and the systemic exposure of pirfenidone compared to theoral administration. Even if compared with dose which does not revealphotodermatosis by taking orally, blood level after inhalation of theformulation 1 shows notably low value. This suggests that it becomespossible for application of this pharmaceutical technology to raiseeffect in lung local part of this agent, and to reduce remarkably therisk of onset of the side effect, photodermatosis, further.

PK parameters of plasma and tissues on PFD in rats after oralintratracheal administrations C_(max) AUC_(0→∞) (plasma, μg/mL; (plasma,h · μg/mL; Samples tissues, μg/g tissue) t_(1/2) (h) tissues, h · μg/gtissue) MRT (h) Plasma PFD-RP (300 μg-PFD/rat, i.t.) 0.307 ± 0.039 0.17± 0.02 0.0835 ± 0.011  0.261 ± 0.011 PFD (30 mg/kg, p.o.) 19.7 ± 0.930.33 ± 0.02 14.1 ± 0.92 0.667 ± 0.094 PFD (160 mg/kg, p.o.) 135 ± 11 0.53 ± 0.03 152 ± 10   1.05 ± 0.075 Skin PFD-RP (300 μg-PFD/rat, i.t.)0.369 ± 0.014 0.24 ± 0.02 0.183 ± 0.029  0.427 ± 0.0051 PFD (30 mg/kg,p.o.) 8.16 ± 0.47 1.07 ± 0.28 11.5 ± 0.51 1.14 ± 0.12 PFD (160 mg/kg,p.o.) 32.9 ± 2.6  1.06 ± 0.24 68.0 ± 1.4   1.70 ± 0.043 Lung PFD-RP (300μg-PFD/rat, i.t.) 0.271 ± 0.035 0.276 ± 0.077 0.136 ± 0.039  0.421 ±0.0080 PFD (30 mg/kg, p.o.) 6.46 ± 0.69 0.799 ± 0.24  6.45 ± 0.43 0.787± 0.16  PFD (160 mg/kg, p.o.) 37.6 ± 5.7  0.766 ± 0.16  52.1 ± 1.0  1.32 ± 0.041 Eyes PFD-RP (300 μg-PFD/rat, i.t.) 0.202 ± 0.19  0.266 ±0.059 0.120 ± 0.030  0.554 ± 0.0084 PFD (30 mg/kg, p.o.) 3.95 ± 0.300.668 ± 0.18  8.33 ± 0.39 1.06 ± 0.13 PFD (160 mg/kg, p.o.) 26.0 ± 2.6 1.06 ± 0.27 58.8 ± 1.3   1.93 ± 0.051 Each parameter was calculated onthe basis of concentration-time curves in plasma and tissues.i.t.:intratracheal administration; and p.o.: oral administration. Each valuerepresents mean ± S.E. for 4-8 rats. PFD-RP: Pirfenidone RespirablePowder PFD: Pirfenidone

EXAMPLE 7

Pharmacokinetics 2 of Pirfenidone at the Time of Air a Administration ofthe Formulation 1

Similarly to Example 5, single-dose administrations of pirfenidoneorally and the formulation 1 by inhalation were performed in rats, andthe amount of transmigration of pirfenidone to each tissue was monitoredby UPLC/ESI-MS. Results are shown in FIG. 7. When compared in dose (160mg/kg) having an anti-inflammatory activity, while the amount ofskin-transmigration of pirfenidone in 1 hour after administration wasabout 50 ng/g-tissue via inhalation (1 mg/kg), the amount via oraladministration (160mg/kg) was about 20 μg/g-tissue. From this, while theamount of medication in inhalation is 1/160 in the case of oraladministration, the amount of skin transmigration in inhalationdecreases to 1/400 of oral formulation. Significant reduction of theamount of skin transmigration of pirfenidone like this suggests largemitigation of side effects by the present invention. Thus, therespirable formulation of the present invention has an excellent effect.

Pirfenidone Pharmacokinetics (3) at the Time of Airway Administration ofthe Formulation 1

Results of having monitored the amount of skin transmigration ofpirfenidone in repeated-dose administrations by oral and inhalation areshown in FIG. 8. Although a temporary elevation of the pirfenidoneconcentration in the skin was observed by pirfenidone oraladministration (30, 160 mg/kg) also in repeated-dose administrations inevery 12 hours, the elevation disappeared in about 6 hours afteradministration. In repeated-dose administrations, pirfenidone did notshow any accumulation trend. At the time of inhalation of theformulation 1, lower skin transitionality was observed more remarkablythan the time of administration of oral dose (30 mg/kg) which does notshow photodermatosis, and similarly, no accumulation trend was shown.From this, the systemic side effect is considered to be avoidable evenwhen the respirable formulation is used repeatedly.

INDUSTRIAL APPLICABILITY

The present invention provides the powder formulation which reduces sideeffect risk of medicine having a side effect of a drug-inducedphotodermatosis and increases therapeutic effect, and the method forproducing the same. Since the powder formulation of the presentinvention makes inhalation therapy possible by the ability of easyaerosolizability and thus increases pharmacological effect in lung localpart, the reduction of dose becomes possible. The skin transmigration ofthe aforementioned medicine can be controlled with a lung specificdelivery technology, and thus, photodermatosis, a side effect, can becontrolled.

1. A powder formulation comprising (i) micronized particles with a meanparticle diameter of 20 μm or less comprising (i-1) a drug showing aside effect of drug-induced photodermatosis and (i-2) an excipient, and(ii) a carrier with a mean particle diameter of 10˜200 μm.
 2. The powderformulation according to claim 1, wherein the drug showing a side effectof drug-induced photodermatosis is 1 or 2 or more selected from thegroup consisting of antibiotics, anticancer drug, antiepileptic drug,antidepressant, antifungal, antihistamine, antimalarial, gout drug,psychotropic drug, cardiovascular remedy, diuretic, antilipemic,non-steroid anti-inflammatory agent, phototherapy agent, letinoid, andpulmonary fibrosis treating agent.
 3. The powder formulation accordingto claim 1, wherein the drug showing a side effect of drug-inducedphotodermatosis is a pulmonary fibrosis treating agent.
 4. The powderformulation according to claim 1, wherein the drug showing side effectsof drug-induced photodermatosis is pirfenidone.
 5. The powderformulation according to claim 1, wherein the micronized particle andthe carrier form a complex.
 6. The powder formulation according to claim5, wherein a particle diameter of the micronized particle is smallerthan a mean particle diameter of the carrier.
 7. The powder formulationaccording to claim 1, wherein the excipient and/or the carrier aresaccharides.
 8. The powder formulation according to claim 7, whereinsaccharides are lactose.
 9. The powder formulation according to claim 1,wherein the excipient and/or the carrier are sugar alcohols.
 10. Thepowder formulation according to claim 9, wherein the sugar alcohols areerythritol.
 11. The powder formulation according to claim 1, wherein theexcipient is macromolecular polymers.
 12. The powder formulationaccording to claim 1, wherein the excipient is erythritol and thecarrier is lactose.
 13. The powder formulation according to claim 1,wherein a ratio between the drug showing side effects of drug-inducedphotodermatosis and the excipient is in the range of 1:5000˜10:1 inweight ratio.
 14. The powder formulation according to claim 1, whereinthe ratio between the micronized particle and the carrier is in therange of 1:100˜10:1 in weight ratio.
 15. The powder formulationaccording to claim 1, wherein a mean diameter of the micronizedparticles is in the range of 1˜9 μm.
 16. The powder formulationaccording to claim 1, wherein the powder formulation is a transpulmonaryinhalation formulation.
 17. The powder formulation according to claim 4,wherein the drug-induced photodermatosis of pirfenidone has been reducedas compared with an oral administration formulation.
 18. A process forproducing the formulation according to claim 1, wherein the micronizedparticles with a mean particle diameter of 20 μm or less comprising adrug showing side effects of drug-induced photodermatosis and anexcipient are mixed with a carrier having a particle diameter of 10˜200μm.
 19. The process according to claim 18, wherein the micronizedparticles are prepared by mixing the drug showing side effects ofdrug-induced photodermatosis and the excipient, and micronizing themixture by a jet mill.
 20. The process according to claim 19, whereinthe micronized particles and the carriers are mixed in a container madefrom nylon or polyethylene.
 21. The process according to claim 18,wherein the micronized particle and the carrier form a complex.
 22. Aninhalation formulation obtained by the process according to claim 18.